Prenatal Alcohol Exposure Images Provide Insight Into FAS

T years have passed since the damaging effects of heavy prenatal alcohol exposure1 on children were first noted in the United States (Jones et al. 1973). A con­ sistent pattern of facial malformations, growth retardation, and varying degrees of central nervous system dysfunction became known as fetal alcohol syndrome (FAS). During an autopsy, the brain of an infant who died at 5 days of age was found to be extremely abnormal (Jones and Smith 1975). The infant, whose condition was one of the first to be diag­ nosed as FAS, had a small brain that was missing the corpus callosum (see figure 1 for a description and diagram of this and other brain areas), a structure that allows information to be transmitted between the two brain hemispheres. During normal embryological development, the nerve cells and the cells that give them structural support migrate to their appropriate posi­

T wenty years have passed since the damaging effects of heavy prenatal alcohol exposure 1 on children were first noted in the United States (Jones et al. 1973). A con sistent pattern of facial malformations, growth retardation, and varying degrees of central nervous system dysfunction became known as fetal alcohol syndrome (FAS). During an autopsy, the brain of an infant who died at 5 days of age was found to be extremely abnormal (Jones and Smith 1975). The infant, whose condition was one of the first to be diag nosed as FAS, had a small brain that was missing the corpus callosum (see figure 1 for a description and diagram of this and other brain areas), a structure that allows information to be transmitted between the two brain hemispheres. During normal embryological development, the nerve cells and the cells that give them structural support migrate to their appropriate posi 1 Mothers of children mentioned in this article are known to have consumed substantial amounts of alcohol during their pregnancies. However, terms such as "heavy prenatal exposure" and "heavy drinkers," as they are used in the article, do not refer to a specific amount of alcohol. It is not known exactly how much the women drank during their pregnancies. tions in the brain. In this infant, the autop sy showed that throughout the brain tissue, there were cells, which could be differenti ated by appearance, that had settled in inappropriate places. Other reports of brain anomalies in children with FAS include increased fluid in the brain, or hydrocephalus; abnormali ties of specific areas of the brain, such as the corpus callosum and cerebellum; and evidence of disorganized cell migration during development (Clarren 1986). Some of these findings have been supported by research that uses animal models of pre natal alcohol exposure. Rats and mice exposed to alcohol before birth have been shown to have numerous abnormalities in the brain, including an abnormally small head (microcephaly); altered migration of brain cells, or neurons; and abnormalities of the cerebellum (Miller 1993;West and Pierce 1986). The cerebellum is the struc ture responsible for coordination of move ment and posture and is also believed to have a role in some aspects of cognition.

MAGNETIC RESONANCE IMAGING
Recently, new technology has allowed researchers to use a noninvasive tech nique to look at brains of living children. Magnetic resonance imaging (MRI) pro duces xraylike pictures of the brain without using radiation. MRI works like Cerebrum Largest portion of the brain, including the cerebral hemi spheres (cerebral cortex and basal ganglia); involved in controlling consciousness Neocortex and voluntary processes Outermost portion of the cerebral cortex that con-Corpus Callosum tains the most structurally A bundle of fibers connect-complex brain tissue ing the brain's hemispheres Diencephalon Hippocampus • Septal area-related to the Part of the limbic system, limbic system, which is inwhich is involved in emotional volved in emotional aspects aspects of survival behavior; of survival behavior also plays a role in memory • Thalamus-a communica tion center that relays in formation to the cerebral A group of structures lying deep cortex in the brain involved in movement • Hypothalamus-important in maintaining the body's internal environment, or homeostasis, through the receipt of sensory and chemical input

Cortex
Outer layer of gray matter covering the surface of the cerebrum and the cerebellum Cerebellum Basal Ganglia and cognition Involved in maintenance of posture, balance, and coordination

Figure 1
Areas of the brain that can be damaged in utero by maternal alcohol consumption.
this: a large magnet causes the atoms in the brain to line up in a consistent fashion. An electromagnetic signal then passes through the magnetic field and provides energy that is absorbed by the aligned atoms. When the electromagnetic signal is discontinued, the atoms release measur able amounts of energy. Different tissues in the brain, such as gray matter and white matter, that have different chemical com positions absorb, and thus release, energy in different ways. For example, the corpus callosum, which is primarily white matter, is distinguishable on an MRI from the cere bellum, which is mainly gray matter. These energy signals are converted to pictures of the brain (Jernigan 1990). Magnetic resonance images can appear as three dimensional pictures or can be divided into twodimensional "slices" of specific areas of interest. This article addresses the use of MRI in ongoing research on brain structure and function in FAS.

RESEARCH FINDINGS
In continuing research, we have conduct ed MRI evaluations on 12 children whose mothers were known to consume large amounts of alcohol while pregnant; 4 of the children have been subjected to de tailed quantitative evaluations. In these four children, the volumes of particular brain areas were determined for compari son with the volumes of these areas in normal, healthy children. Two of these cases were adolescents with a clinical diagnosis of FAS (Mattson et al. 1992). The other two cases were adolescents with a known history of heavy in utero alcohol exposure but who lacked suffi cient characteristics to warrant the clinical diagnosis of FAS (Mattson et al. in press a). These two cases are referred to as "PEA," for prenatal exposure to alcohol. MRI evaluations revealed that all four children were microcephalic. The volume of each adolescent's brain was, on aver age, about 25 percent smaller than the brain of a healthy child of the same age. Similarly, the volume of the cerebellar area was smaller than that of a healthy child by approximately 20 percent.

EFFECTS ON BASAL GANGLIA
One group of structures studied in the four children that appeared to be particu larly affected was the basal ganglia. The basal ganglia lie deep in the brain and are involved in both movement and cogni tion; there are extensive nerve fiber con nections between the basal ganglia and the outer portion of the brain, or cortex.
We controlled for the overall reduction in the volume of the brain in the children by looking at the volume of each brain part in proportion to its overall volume. Even with this method of control, the basal ganglia were still reduced in size, compared with those of both normal and mentally retarded control subjects. There was little difference in the volumes of the overall brain and the basal ganglia be tween the two children with FAS and the two with PEA.
The volume of the diencephalon (an area of the brain that encompasses the thalamus, which is the brain's relay cen ter; the hypothalamus, which is responsi ble for regulating the pituitary gland; and the septal area, which is related to the limbic system) was reduced in all four children. However, when we controlled for the overall reduction in brain size, an interesting difference emerged between the children with FAS and those with PEA. The two children with FAS showed a reduction in the proportional size of the diencephalon, whereas even though the children with PEA showed a reduction, the ratio remained within the normal range for healthy control subjects. Thus, the diencephalon may only be reduced in proportional volume in severe cases of alcohol exposure (e.g., FAS), whereas the proportional size of the basal ganglia compared with total brain volume may be reduced following heavy gestational alcohol exposure, both for PEA and for FAS subjects.

EFFECTS ON THE CORPUS CALLOSUM
As mentioned above, the corpus callosum connects the hemispheres of the brain and allows information to be transmitted be tween them. In general, the right hemi sphere of the brain controls the left side of the body, and the left hemisphere of the brain controls the right side of the body. The corpus callosum allows both hemi spheres to know what happens in both sides of the body. The first child with FAS that we assessed using MRI, who was one of the two FAS children evaluat ed in the basal ganglia and diencephalon research, did not have a corpus callosum. The corpus callosum does not appear to be essential for normal functioning, but its absence is a relatively rare abnormality that occurs in about 0.1 percent of the general population. In the learning dis abled and mentally retarded population, absence of the corpus callosum is more common, occurring in about 2 percent of that population (Jeret et al. 1986). Two other children in our sample lack the cor pus callosum. Figure 2 shows an MRI scan of a child with FAS who lacks a corpus callosum as well as a scan of a child with FAS who shows thinning in the back part of the corpus callosum.
The corpus callosum also was investi gated in 10 children whose mothers were heavy drinkers during their pregnancies. The overall area of the corpus callosum, taken using twodimensional slices of mag netic resonance images, is smaller in child ren in the alcoholexposed group than in a control group of normal children who were matched to them for age and gender. In addition, when we divided the corpus callos um into regions, a standard method for analyzing this structure, four out of the five regions were significantly smaller in the alcoholexposed children than the same regions in the normal control group children.
Because the alcoholexposed children have smaller brains overall, we also looked at their corpora callosa in proportion to their overall brain sizes, as we had done for the basal ganglia and diencephalon. Even in this assessment, the alcoholexposed group still showed three corpus callosum regions that were significantly smaller than those in the normal control group. At this time, we do not fully understand the causes, nor can we predict the consequences, of this size difference. It may be that in the three pro portionally reduced regions, there are fewer axons, or nerve fibers, crossing between the hemispheres, or it is possible that there are a normal number of extraordinarily small diameter axons crossing. In either case, one consequence of a reduced corpus callosum might be abnormal development of the division of responsibilities that generally takes place between the hemispheres.

ASSOCIATION OF MRI FINDINGS WITH PRENATAL ALCOHOL EXPOSURE
The information gained from MRI should help researchers make connections be tween the behavioral and cognitive char acteristics, such as memory deficits, that are associated with heavy prenatal alcohol exposure and specific structural defects in the brain.
One example that relates brain struc ture to function in adults is Huntington's disease (HD). It is an inherited disorder associated with damage to the basal gan glia that causes motor abnormalities as well as memory problems, or dementia. The problems with memory include diffi culty in retrieving stored information. For example, on the California Verbal Learn ing Test (CVLT), a test that measures verbal learning and memory, patients with HD show limited ability in learning and immediately recalling a word list. Specif ically, they display repetitive (persevera tive) errors; are insensitive to proactive interference (which is when old informa tion interferes with the learning of new information); and perform better when asked, in a yes/no format, whether certain words appeared on the list.
The CVLT for children has been given to FAS children, and the results suggest a pattern of performance somewhat similar to that of the HD patients (Mattson et al. 1991). Because HD patients' disabilities are associated with basal ganglia damage, and MRI findings show FAS children to have proportionally reduced basal gan glia, the similarities between the two disorders suggest the possibility that the smaller basal ganglia size may affect FAS children's memory problems. The basal ganglia are known to play a role in a person's ability to remember where things are in space, in a person's goaldirected behavior, and in a person's ability to successfully transfer from one activity or task to the next (Cote and Crutcher 1991). Children with FAS have been reported to have deficits in memory, specifically spatial memory; to have diffi culty learning the consequences of their actions; and to be perseverative. These behaviors may be related to the small volume of the basal ganglia that is seen in children with histories of heavy prenatal alcohol exposure, not just in those with FAS (Mattson et al. in press). Other brain areas also may be involved in the behav ioral effects that result from alcohol exposure. For example, the diencephalon is reduced in FAS children (although it is not in PEA children), and this may con tribute to their generally poorer behav ioral functioning, compared with the PEA children.
The findings regarding the corpus cal losum are interesting as well. The three regions of the corpus callosum that are reduced in prenatally alcoholexposed children are, in healthy people, thought to contain nerve fibers from several parts of the brain, including the frontal region, involved in complex integration of other brain systems; the posterior parietal region, involved in visual and spatial functioning; the temporal region, involved in memory; and the occipital region, involved in vi sion. Interestingly, these corpus callosum regions also are reduced in children with attentiondeficit hyperactivity disorder (ADHD) (Hynd et al. 1991). Deficits in attention, such as becoming easily dis tracted from a task, and increased activity have long been considered signs of FAS (Streissguth 1986). In addition, the specif ic brain regions that are reduced in chil dren in both the ADHD and the FAS groups may reflect some common under lying dysfunction in brain development that appears in children with either mala dy. For example, children with FAS or ADHD may have underlying deficiencies related to the frontal regions of the brain, as evidenced by their motor persistence, such as hyperactivity, and their difficulty inhibiting unwanted behaviors.

CONCLUSIONS
MRI allows researchers to view the brains of living children who have been exposed to large amounts of alcohol in the womb. Ultimately, the patterns of malformations seen in the brain can be related to the be havioral profiles of children with FAS and other alcoholrelated birth defects. Cor relating brain structure to function may make it easier to understand the mecha nisms behind the potentially devastating effects that alcohol has on the developing fetus. ■